Combination Therapy for Bipolar Disorder

ABSTRACT

Treatment regimens for mood disorders that include administration of buprenorphine, alone or in combination with additional pharmacological agents are described. Specifically, treatment regimens that alleviate racing thoughts associated with bipolar disorder, and pharmaceutical compositions and kits for use therein are described. Dosing regimens, compositions, and kits including buprenorphine for treating mania associated with opioid withdrawal are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 61/044,312 filed on Apr. 11, 2008 and U.S. Provisional PatentApplication Ser. No. 61/050,738 filed on May 6, 2008, each of which ishereby incorporated by reference in its entirety.

FIELD

Treatment regimens for mood disorders that include administration ofbuprenorphine, alone or in combination with additional pharmacologicalagents are described. Specifically, treatment regimens that alleviateracing thoughts associated with bipolar disorder, and pharmaceuticalcompositions and kits for use therein are described. The buprenorphineand other pharmacological agents can be administered at therapeutic orsubtherapeutic doses to treat the racing thoughts. Dosing regimens,compositions, and kits including buprenorphine for treating maniaassociated with opioid withdrawal are also described.

BACKGROUND

Bipolar disorder, also known as manic-depressive illness, is a disorderthat causes unusual shifts in a individual's mood, energy, and abilityto function. Different from the normal ups and downs that peopleexperience, the symptoms of bipolar disorder are generally severe. Theycan result in damaged relationships, poor job or school performance, andeven suicide.

Bipolar disorder typically develops in late adolescence or earlyadulthood. However, some people have their first symptoms duringchildhood, and some develop them late in life. Bipolar disorder is along-term illness that usually requires management throughout anindividual's life.

Bipolar disorder typically causes dramatic mood swings, from overlyelated (“high”) and/or irritable to sad and hopeless, and then backagain, often with periods of normal mood in between. Severe changes inenergy and behavior oftentimes are experienced with these changes inmood. The periods of highs and lows are referred to as episodes of maniaand depression.

Signs and symptoms of mania (or a manic episode) may include thefollowing: increased energy, activity, and restlessness; excessively“high,” overly good, euphoric mood; extreme irritability; racingthoughts and talking very fast, jumping from one idea to another;distractibility (e.g., difficulty concentrating); decreased need forsleep; unrealistic belief in one's abilities and powers; poor judgment;spending sprees; a lasting period of behavior that is different fromusual; increased sexual drive; abuse of drugs (particularly cocaine,alcohol, and sleeping medications); and provocative, intrusive, oraggressive behavior. A manic episode may be diagnosed if elevated moodoccurs with three or more of the other symptoms most of the day, nearlyevery day, for one week or longer.

Signs and symptoms of depression (or a depressive episode) may includethe following: lasting sad, anxious, or empty mood; feelings ofhopelessness or pessimism; feelings of guilt, worthlessness, orhelplessness; loss of interest or pleasure in activities once enjoyed;decreased energy, a feeling of fatigue or of being “slowed down”;difficulty concentrating, remembering, or making decisions; restlessnessor irritability; sleeping too much, or difficulty sleeping; change inappetite and/or unintended weight loss or gain; chronic pain or otherpersistent bodily symptoms that are not caused by physical illness orinjury; and thoughts of death or suicide, or suicide attempts. Adepressive episode may be diagnosed if five or more of these symptomslast most of the day, nearly every day, for a period of two weeks orlonger.

A mild to moderate level of mania is generally referred to as hypomania.Hypomania may feel good to the individual who experiences it and mayeven be associated with good functioning and enhanced productivity.Thus, even when family and friends learn to recognize the mood swings aspossible bipolar disorder, the individual may deny that anything iswrong. Without proper treatment, however, hypomania can become severemania or can switch into depression.

Sometimes severe episodes of mania or depression include symptoms ofpsychosis. Common psychotic symptoms are hallucinations (hearing,seeing, or otherwise sensing the presence of things not actually there)and delusions (false, strongly held beliefs not influenced by logicalreasoning or explained by an individual's usual cultural concepts).Psychotic symptoms in bipolar disorder tend to reflect the extreme moodstate at the time. For example, delusions of grandiosity, such asbelieving one is the President or has special powers or wealth, mayoccur during mania; delusions of guilt or worthlessness, such asbelieving that one is ruined and penniless or has committed someterrible crime, may appear during depression.

It may be helpful to think of the various mood states in bipolardisorder as a spectrum or continuous range. At one end is severedepression, above which is moderate depression and then mild low mood,which many people call “the blues” when it is short-lived but is termed“dysthymia” when it is chronic. Then there is normal or balanced mood,above which comes hypomania (mild to moderate mania), and then severemania.

In some people, however, symptoms of mania and depression may occurtogether in what is called a mixed bipolar state. Symptoms of a mixedstate often include agitation, trouble sleeping, a significant change inappetite, psychosis, and suicidal thinking. An individual may have avery sad, hopeless mood while at the same time feeling extremelyenergized.

Bipolar disorder may also initially present as a problem other thanmental illness. For instance, it may surface as alcohol or drug abuse,poor school or work performance, or strained interpersonalrelationships. Such problems in fact may be signs of an underlyingbipolar disorder.

The classic form of the illness, which involves recurrent episodes ofmania and depression, is called bipolar I disorder. Some individuals,however, never develop severe mania but instead experience milderepisodes of hypomania that alternate with depression; this form of theillness is called bipolar II disorder. When four or more episodes ofillness occur within a 12-month period, an individual is said to haverapid-cycling bipolar disorder. Some individuals experience multipleepisodes within a single week, or even within a single day.

Bipolar disorder may be treated with medication and psychosocialtherapy. For example, medications known as mood stabilizers may beprescribed. In general, individuals with bipolar disorder continuetreatment with mood stabilizers for years. Other medications may beadded when necessary, typically for shorter periods, to treat episodesof mania or depression that break through despite the mood stabilizer.

However, despite the use of mood stabilizers, drugs, e.g., alcohol,prescription drugs, or other illicit drugs, are often used as a form of“self-medication” in order to counteract unpleasant psychologicalsymptoms (such as racing thoughts), which often leads to abuse of thesedrugs. Patients with bipolar disorder and other psychiatric disordersmay also demonstrate somatization and therefore seek out “painmanagement” doctors, because the analgesics, hypnotics and stimulantscommonly prescribed in this context can help to temporarily relieve orcontrol dysphoric symptoms experienced in part as physical pain.

The high rates of drug abuse amongst patients with psychiatric disordershas been documented. See, e.g., Cerullo and Strakowski, Subst AbuseTreat Prey Policy (2007) 2:29. For example, Cerullo and Strakowskireport that the lifetime history of any drug abuse or dependence is 84%for anti-social personality disorder, 62% for bipolar disorder types Iand II, and 47% for schizophrenia, compared with 27.2% for majordepressive disorder and 17% for the general population.

However, drug abuse, e.g., opioid abuse, and opioid withdrawal, canactually worsen mood symptoms and significantly complicate the courseand prognosis of bipolar disorder or any other psychiatric illness,resulting in increased suffering, disability, and costs through morefrequent and prolonged affective episodes, decreased compliance withtreatment, a lower quality of life, and increased suicidal behavior.

Accordingly, new regimens for treating unpleasant and/or difficult totreat symptoms of psychiatric disorders, especially bipolar disorderwould be useful. Treatment regimens that address drug abuse andwithdrawal, e.g., opioid abuse and withdrawal, would also be useful. Inparticular, treatment regimens that are provided as kits would bedesirable.

SUMMARY

Described here are treatment regimens and compositions and kits for usetherein that may be beneficial in stabilizing mood, increasingmedication compliance, and preventing drug abuse in subjects withbipolar disorder. The treatment regimens may achieve mood stabilizationby administering a partial opioid agonist, e.g., buprenorphine, in apredetermined fashion. For example, when a plurality of buprenorphinedoses are administered per day, the first dose may be higher than anyadditional dose given. In one variation, a morning dose ofbuprenorphine, e.g., a dose administered at 6 am, may be higher than abuprenorphine dose given in the evening, e.g., a dose administered at 6pm, or in the late evening, e.g., at 12 am (midnight). The first dose ofbuprenorphine may range from about 1.0 mg to about 32 mg. For example,the first dose may be about 1.0 mg, about 2.0 mg, about 4.0 mg, about8.0 mg, about 16 mg, about 24 mg, or about 32 mg of buprenorphine. Thelower dose of administered buprenoprhine may range from about 0 mg toabout 4.0 mg. For example, the first administered dose may be about 0mg, about 0.5 mg, about 1.0 mg, about 2.0 mg, or about 4.0 mg. It isunderstood that any suitable number of doses may be administered. Forexample, one dose, two doses, three doses, or four doses may beadministered. In some variations, the treatment regimens may includerapidly decreasing the buprenorphine dose over the course of a day. Inother variations, a gradual decrease in the buprenorphine dose isemployed (over a day).

The treatment regimens may be useful in treating mania associated withopioid withdrawal. Here it is the belief of the inventors that when ahigher dose of buprenorphine is taken in the evening or late evening(e.g., to treat opioid withrawal), it acts as a mood destabilizer andthus, kindles mania or mania-like symptoms in this patient population.In another variation, the treatment regimens may be beneficial inalleviating racing thoughts during the depressive phase of bipolardisorder. The treatment regimens may further include one or more activeagents (supplemental agents), for treating comorbid conditionsassociated with bipolar disorder.

As used herein, a “manic episode” is defined by criteria set forth inthe DSM-IV (Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition, 2000, American Psychiatric Association, Washington,D.C), which is hereby incorporated herein by reference for all purposes,as a distinct period of abnormally and persistently elevated, expansive,or irritable mood, lasting at least one week wherein three (or more) ofthe following symptoms have persisted and have been present to asignificant degree:

-   -   (1) inflated self-esteem or grandiosity    -   (2) decreased need for sleep (e-g., feels rested after only 3        hours of sleep)    -   (3) more talkative than usual or pressure to keep talking    -   (4) flight of ideas or subjective experience that thoughts are        racing    -   (5) distractibility (i.e., attention too easily drawn to        unimportant or irrelevant external stimuli)    -   (6) increase in goal-directed activity (either socially, at work        or school, or sexually) or psychomotor agitation    -   (7) excessive involvement in pleasurable activities that have a        high potential for painful consequences (e.g., engaging in        unrestrained buying sprees, sexual indiscretions, or foolish        business investments)

The mood disturbance is sufficiently severe to cause marked impairmentin occupational functioning or in usual social activities orrelationships with others, or to necessitate hospitalization to preventharm to self or others, or there are psychotic features. The symptomsare not due to the direct physiological effects of a substance (e.g., adrug of abuse, a medication, or other treatment) or a general medicalcondition (e.g., hyperthyroidism).

A “mixed episode” is observed when criteria are met both for a manicepisode (see above) and for a major depressive episode, as defined inthe DSM-IV, nearly every day during at least a one week period and themood disturbance is sufficiently severe to cause marked impairment inoccupational functioning or in usual social activities or relationshipswith others, or to necessitate hospitalization to prevent harm to selfor others, or there are psychotic features. As with a manic episode, thesymptoms are not due to the direct physiological effects of a substance(e.g., a drug of abuse, a medication, or other treatment) or a generalmedical condition (e.g., hyperthyroidism).

A “hypomanic episode” is defined by the DSM-IV as a distinct period ofpersistently elevated, expansive, or irritable mood, lasting throughoutat least four days, that is clearly different from the usualnondepressed mood. During the period of mood disturbance, three (ormore) of the symptoms listed above for “manic episode” above, havepersisted and have been present to a significant degree. The episode isassociated with an unequivocal change in functioning that isuncharacteristic of the individual when not symptomatic. The disturbancein mood and the change in functioning are observable by others. Theepisode is not severe enough to cause marked impairment in social oroccupational functioning, or to necessitate hospitalization, and thereare no psychotic features. The symptoms are not due to the directphysiological effects of a substance (e.g., a drug of abuse, amedication, or other treatment) or a general medical condition (e.g.,hyperthyroidism).

As used herein, the phrase “opioid withdrawal” refers to a variety ofsigns and complaints appearing with the abrupt removal of, or a rapiddecrease in the regular dosage of opioids. The symptoms stop when anopioid agonist is taken again. Physical manifestations may includesweating, nausea, yawning, chills, diarrhea, papillary dilation,piloerection, tachycardia, increased blood pressure, hypersensitivity topain, stomach cramps, and muscle cramps. Psychological manifestations ofopioid withdrawal observed may include dysphoria, restlessness,irritability, anxiety, and depression. Onset often begins within 6-24hours from last opioid use.

The terms “treating” or “alleviating” interchangeably refer to delayingthe onset of, retarding or reversing the progress of, or preventingeither the disease or condition to which the term applies, or one ormore symptoms of such disease or condition.

The term “patient,” “subject,” or “individual” interchangeably refer toa mammal, for example, a domesticated mammal (canine or feline), alaboratory mammal (murine, rattus, lagomorpha), or a human.

A variation of the methods described here includes treating maniaassociated with opioid withdrawal in a subject by administering a firstdose of a kappa opioid and at least one additional dose of the kappaopioid to the subject according to a predetermined dosage regimen, wherethe at least one additional dose is less than the first dose. The firstdose may be administered in the morning, e.g., at 6 am or between about6 am and 9 am, and the at least one additional dose may be administeredin the afternoon, e.g., at 12 pm (noon) or between about 12 pm and 3 pm,evening, e.g., at 6 pm or between about 6 pm and 9 pm, or late evening,e.g., at 12 am (midnight). The kappa opioid may be a kappa receptorantagonist including, but not limited to, 5′-guanidinonaltrindole,buprenorphine, norbinaltorphimine, JDTic, and combinations thereof. Inone variation, the kappa receptor antagonist is buprenorphine. Thebuprenorphine may be administered in doses of about 0.5 mg, about 1.0mg, about 2.0 mg, about 8.0 mg, about 16 mg, about 24 mg, about 32 mg,or combinations thereof. In some variations, a subtherapeutic dose ofbuprenorphine is administered.

By “subtherapeutic dose” it is meant a dose of a kappa opioid, e.g.,buprenorphine, either as an administered dose of the kappa opioid, oractual level of the kappa opioid in a subject that functionally isinsufficient to elicit the intended pharmacological effect in itself(e.g., analgesia, pain relief, reversal of opioid withdrawal symptoms,reduction of psychotic symptoms, prevention of epileptic seizure, etc.),or that quantitatively is less than the established therapeutic dose forthat particular kappa opioid (e.g., as published in a referenceconsulted by a individual of skill, for example, doses for apharmacological agent published in the Physicians' Desk Reference,62^(nd) Ed., 2008, Thomson Healthcare or Brunton, et al., Goodman &Gilman's The Pharmacological Basis of Therapeutics, 11^(th) edition,2006, McGraw-Hill Professional). A “subtherapeutic dose” can be definedin relative terms (i.e., as a percentage amount (less than 100%) of theamount of the kappa opioid conventionally administered). For example, asubtherapeutic dose amount can be about 1% to about 75% of the amount ofkappa opioid conventionally administered. In some variations, asubtherapeutic dose can be about 10%, 20%, 25%, 30%, 50% or 75% of theamount of kappa opioid conventionally administered.

In another variation, the kappa opioid may be a kappa receptor agonistincluding, but not limited to, butorphanol, BRL-52537, cyclazocine,enadoline, GR-89696, HZ-2, ICI-204,448, ketazocine, LPK-26(2-(3,4-Dichlorophenyl)-N-methyl-N-[(1S)-1-(2-isopropyl)-2-(1-(3-pyrrolinyl))ethyl]acetamide),nalbuphine, pentazocine, salvinorin A, spiradoline, tifluadom, U-50488,U-62066, U-69593, and combinations thereof.

The predetermined dosing regimens may administer the first dose of thekappa opioid in the morning and at least one additional dose of thekappa opioid in the evening. In one variation, two or more additionaldoses of the kappa opioid are administered in a gradually decreasingfashion.

In other variations, a second active agent may be administered to helpwith mood stabilization. Exemplary second active agents include withoutlimitation, antipsychotic agents, atypical antipsychotic agents,antiepileptic agents, lithium, P-450 CYP3A4 inhibitors, P-450 CYP2D6inhibitors, CB1 agonists, CB2 agonists or antagonists, salts, and acidsthereof, and combinations thereof. When atypical antipsychotics areemployed, they may include without limitation, aripriprazole,arisulpride (amisulpride), olanzapine, paliperidone, quetiapine,risperidone, ziprasidone, and combinations thereof. The predetermineddosing regimens may be designed so that the second active agent isadministered in the morning or the evening. In some variations, thesecond acitve agent is administered multiple times a day. The secondactive agent may also be administered in a rapidly or graduallyincreasing or decreasing manner throughout the day. In some variations,the second active agent is administered in an increasing manner, i.e.,the morning dose is lower than the evening or late evening dose. Inother variations, the dosing of the second active agent and partialopioid agonist is inverse to one another. In yet further variations, thesecond active agent may be administered so that the highest dose is inthe evening and the lowest dose is in the morning.

Further active agents (supplemental agents) may be administered to treatcomorbid conditions associated with bipolar disorder, a side-effect ofthe second active agent, or another symptom associated with bipolardisorder. The comorbid condition may be a sleep disorder. Exemplarysleep disorders include without limitation, hypoventilation-obesitysyndrome (Picwickian syndrome), idiopathic hypersomnia, narcolepsy,night terrors, parasomnias, primary snoring, sleep apnea, nocturnalsleep-related eating disorder, spousal arousal syndrome, upper airwayresistance syndrome, and combinations thereof. In some variations, thesleep disorder may be due to alcoholism, allergic rhinitis, alteredlight-dark cycles, amphetamine use, antidepressant use, anxiety, asthma,benzodiazepine withdrawal, chronic fatigue syndrome, chronic obstructivepulmonary disease (COPD), chronic pain, cocaine use, compulsivehyperphagia, anorexia, bulimia, anorexia-bulimia, starvation, restrictedcaloric intake, dementia, disturbances in circadian rhythm, dyspnea,edema, eneuresis, fibromyalgia, food intolerance, gastroesophagealreflux, hyperammonemia, hypersensitivity to stimulants, incontinence,infection, inflammatory bowel syndrome, irritable bowel syndrome,modafinil (Provigil® tablet) use, neuromuscular disorders, nocturia ,nocturnal myoclonus, orthopnea, paroxysmal nocturnal dyspnea, pica,Prinzmetal's angina, pruritis, racing thoughts, restless leg syndrome,seizure disorder, sinusitis, sleepwalking, or combinations thereof.

Other comorbid conditions include diabetes mellitus, obesity, andfibromyalgia. An exemplary side-effect of the second active agent may bean extrapyrimidal symptom such as akisthesia.

The kappa opioids, second active agents, and supplemental agents may beprovided in any suitable dosage form. For example, the dosage forms maybe liquid, solid, or semi-solid. They may also be formulated for anysuitable mode of administration, such as, but not limited to, oral,sublingual, buccal, parenteral, intravenous, intramuscular,subcutaneous, topical, inhalation, and needle-free administration. Insome variations, the first dose and the at least one additional dose ofthe kappa opioid are provided in the same dosage form. In othervariations, the first dose and the at least one additional dose of thekappa opioid are provided in different dosage forms. Exemplary dosageforms include without limitation, powders, granules, capsules, films,transdermal patches, buccal patches, sublingual formulations, gums,chewables, oral strips, rapid dissolve tablets, coated tablets,solutions, ointments, creams, and gels. In some instances, thecomposition comprises a sublingual formulation within a rapid dissolvetablet. In other instances, the composition comprises a sublingualformulation surrounded by a buccal patch. In yet further instances, thecomposition comprises a sublingual formulation surrounded by a mouthstrip. It is understood that other composition forms are alsocontemplated.

In some variations, the kappa opioids, e.g., buprenorphine, secondactive agents, and supplemental agents are provided in separate dosageforms and co-administered (administered in combination) with each other,e.g., taken at the same time or sequentially. In other variations, thekappa opioids, e.g., buprenorphine, second active agents, andsupplemental agents are co formulated together, i.e., they are includedin a single dosage form.

The compositions for use with the methods described herein may include apartial opioid agonist, e.g., a kappa-receptor antagonist such asbuprenorphine, and a second active agent in a single dosage form, wherethe second active agent comprises an antipsychotic agent, an atypicalantipsychotic agent, an antiepileptic agent, lithium, naloxone, a P-450CYP3A4 inhibitor, a P-450 CYP2D6 inhibitor, salts and acids thereof, andcombinations thereof. The single dosage form may be a powder, granules,capsules, films, transdermal patches, buccal patches, sublingualformulations, gums, chewables, oral strips, rapid dissolve tablets,coated tablets, solutions, ointments, creams, and gels. In onevariation, the single dosage form comprises a sublingual formulationwithin a rapid dissolve tablet. In some variations, the second activeagent includes an atypical antipsychotic. For example, the atypicalantipsychotic may include aripriprazole, arisulpride, olanzapine,paliperidone, quetiapine, risperidone, ziprasidone, or combinationsthereof.

Kits for treating mania associated with opioid withdrawal that include aplurality of buprenorphine dosage forms and instructions foradministering the dosage forms according to a predetermined dosageregimen are also described. Here the predetermined dosing regimen mayinclude administering a first buprenorphine dose and at least oneadditional buprenorphine dose that is less than the first dose. Thepredetermined dosing regimen may provide that the first dose beadministered in the morning, e.g., at 6 am or between about 6 am and 9am, and the at least one additional dose administered in the afternoon,e.g., at 12 pm (noon) or between about 12 pm and 3 pm, evening, e.g., at6 pm or between about 6 pm and 9 pm, or late evening, e.g., at 12 am(midnight).

The kits may include a housing configured to organize the dosage formsaccording to the predetermined dosing regimen. For example, the housingmay be configured to organize the plurality of dosage forms into morningdosage forms and evening dosage forms. In some variations, the housingmay be configured to organize the plurality of buprenorphine dosageforms according to a rapidly or a gradually decreasing dosing regimen.In yet further variations, the housing may be configured to organize thebuprenorphine dosage forms according to the day of the week to be taken.

The kits may also include a second dosage form having one or more secondactive agents. The second active agent may also help to stabilize themood of the patient. Exemplary second active agents include withoutlimitation, aripriprazole, arisulpride, olanzapine, paliperidone,quetiapine, risperidone, ziprasidone, and combinations thereof. The kitmay further include additional dosage forms that include one or moreadditional agents for treating a comorbid condition. For example, anantihistamine may be useful to include when the comorbid condition is asleep disorder. Dosage forms that include other active agents (e.g., totreat comorbidities) or second active agents (e.g., for moodstabilization) may be organized in the housing similar to theorganization provided for the buprenophine dosage forms, as describedabove.

Also described here are methods for treating a bipolarcondition/disorder and subtypes thereof in a subject experiencing racingthoughts by administering buprenorphine to the subject to alleviate theracing thoughts. Subtypes of a bipolar condition may include withoutlimitation, bipolar I disorder, bipolar II disorder, mixed bipolardisorder, rapid-cycling bipolar disorder, hypomania, cyclothymia, acutemania, drug-induced mania, or drug-induced hypomania. The methods may beapplicable to racing thoughts experienced during a depressive episode(instead of during the manic phase). In some variations, an opioidantagonist is also administered. In other variations, a second activeagent is administered to the subject to help stabilize their mood. Suchagents may include antipsychotic agents, atypical antipsychotic agents,antiepileptic agents, lithium, and salts and acids thereof, andcombinations thereof. Supplemental or additional agents may also beadministered to treat a comorbid condition, a side-effect of the secondactive agent, a symptom associated with the bipolar condition, orcombinations thereof. In other instances, light therapy may be used totreat the racing thoughts, other symptoms associated with the bipolardisorder, a comorbid condition, or a side-effect of the second activeagent.

The kits for treating the symptom of racing thoughts in bipolar disordermay include a plurality of buprenorphine dosage forms, at least onesecond dosage form comprising a second active agent that helps tostabilize mood, e.g., an atypical antipsychotic agent, and instructionsfor taking the dosage forms according to a predetermined dosing regimen.Dosage forms including an opioid antagonist such as naloxone may also beincluded. In some variations, dosage forms having a supplemental oradditional agent for treating a comorbid condition, side-effect ofsecond agent, and/or other symptoms of bipolar disorder may be providedin the kits.

The kits may further include a housing configured to organize the dosageforms according to the predetermined dosing regimen. For example, thehousing may be configured to organize the plurality of dosage forms intomorning dosage forms and evening dosage forms. In some variations, thehousing may be configured to organize the plurality of dosage formsaccording to a rapidly or a gradually decreasing dosing regimen. In yetfurther variations, the housing may be configured to organize the dosageforms according to the day of the week to be taken. The kits may also betailored to treat particular bipolar conditions or subtypes. Forexample, the kits may be tailored to treat bipolar I disorder, bipolarII disorder, mixed bipolar disorders, rapidly-cycling bipolar disorder,acute mania, drug-induced mania, hypomania, cyclothymia, or combinationsthereof.

DETAILED DESCRIPTION

Described herein are treatment regimens and compositions and kits foruse therein that may be beneficial in stabilizing mood, increasingmedication compliance, and preventing drug abuse in subjects withbipolar disorder. As previously stated, the treatment regimens mayachieve mood stabilization by administering a partial opioid agonist,e.g., a kappa-receptor antagonist such as buprenorphine, in apredetermined fashion. The amount and frequency of administration of thepartial opioid agonist will vary depending on such factors as theparticular type of bipolar disorder diagnosed, associated symptomsand/or comorbidities, other medications being taken by the patient, andprevious history of opioid abuse. For example, when a plurality ofbuprenorphine doses are administered per day, the first dose may behigher than any additional dose given. In some variations, a morningdose of buprenophine may be higher than a buprenorphine dose given inthe evening or late evening. For example, a buprenophine doseadministered at 6 am may be higher than a buprenorphine dose given inthe evening, e.g., at 6 pm, or late evening., e.g., at 12 am (midnight).In some variations, the treatment regimens may include rapidlydecreasing the buprenorphine dose over the course of a day. In othervariations, a gradual decrease in the buprenorphine dose is employed(over a day).

The treatment regimens may be useful in treating mania associated withopioid withdrawal. This may be due to the destabilizing effect ofbuprenophine when taken in the evening by patients undergoing opioidwithdrawal treatment. As previously stated, it is the belief of theinventors that when higher doses of buprenorphine are taken in theevening, it acts as a mood destabilizer and thus, kindles mania ormania-like symptoms in this patient population. In another variation,the treatment regimens may be beneficial in alleviating racing thoughtsduring the depressive phase of bipolar disorder.

A variety of studies have implicated buprenorphine in the induction ofmania or manic episodes. See, e.g., Jagadheesan and Muirhead, Aust NZ JPsychiatry (2004) 38(7):560; Leza, et al., Gen Pharmacol (1991)22(2):293-6; and Robertson and Taylor, J Feline Med Surg. (2004)6(5):321-33. However, contrary to the published literature, theinventors have found that kappa opioids such as buprenorphine, eitheradministered alone or in combination with other active agents, isefficacious in mood stabilization when a lower dose is administered inthe evening, and also efficacious in alleviating racing thoughtsassociated with the depressed phase(s) of bipolar disorder. Accordingly,buprenorphine may be useful in treating mania associated with opioidwithdrawal. The inventors have also found that buprenorphineadministration may improve patient compliance with prescribed medicationregimes by better stabilizing their bipolar symptoms, and in someinstances, may improve compliance by reducing the number of medicationsneeded to effectively treat bipolar disorder symptoms.

For example, bipolar disorder patients are prone to narcotic abusebecause when initially taken, the narcotics elevate their mood. However,when the narcotic wears off, the patients become even more depressed,resulting in a desire to take more narcotics, which then wear off, etc.,resulting in an oscillating behavioral pattern that negatively effectsthe course of their bipolar disorder. For instance, patients withco-occurring substance use may have more prolonged affective episodesand may generally be less compliant with treatment. In some cases, moremood stabilizer needs to be prescribed to help control symptoms.Contrastingly, the inventors have found that bipolar disorder patientsbeing administered buprenorphine according to the dosing regimensdescribed herein may be less likely to take other narcotic substances.Given that buprenorphine administration has been found to alleviatesymptoms such as anxiety, irritability, and racing thoughts, patients onbuprenorphine therapy may be less predisposed to self-medicate withbenzodiazepines. They may also be less likely to take antidepressants toalleviate depressive symptoms. This is also beneficial becauseantidepressants have been associated with triggering mania.

Compliance may also be reduced due to the detrimental side-effects thatmay be experienced with conventional bipolar disorder treatments.Currently, mania is treated with mood stabilizers and antipsychoticmedications. Both classes of medications are accompanied withpotentially harmful side effects. Lithium, used as a mood stabilizer,can produce sometimes significant weight gain, acne with scarring,thinning of hair, and pronounced tremor. Administration of antipsychoticmedications can result in the development of extrapyramidal symptoms(EPS) consisting of extreme motor restlessness (akathisia), prolongedmuscle contraction (dystonia), parkinsonism and repetitive, involuntarypurposeless movements such as grimacing, blinking, lip smacking,puckering and pursing (tardive dyskinesia) which have a significantimpact on tolerability and adherence in addition to impacting function.The use of antipsychotics has also been associated with neurolepticmalignant syndrome, a life threatening neurological disorder. These sideeffects render compliance difficult. This may be especially true forindividuals with co-occurring substance abuse; a significant proportionof individuals suffering from mania and/or bipolar disorder.

Compliance may also be affected by sleep disturbance. Sleep problems inbipolar disorder are universal and persistent; they represent both asymptom of the condition and a cause. Bipolars tend to exhibit impairedsleep efficiency, higher levels of anxiety and fear about poor sleep,and a tendency to misperceive that the sleep they are getting isinadequate. See, e.g., Harvey et al., Am J Psychiatry 162:50-57, January2005. The underlying cause of their anxiety is often awareness thatsleep loss can herald or intensify periods of manic or hypomanicactivity. This anxiety may then serve to perpetuate the insomnia whichin turn exacerbates the disease. The prevalence of opioid andbenzodiazepine abuse is partially explainable in terms of theeffectiveness of these drugs on promoting sleep. Medicines other thanfull opioid agonists and benzodiazepines which promote sleep maytherefore have a particularly palliative effect in this population bothas abortive therapy during a manic or hypomanic episode and asprophylactic therapy to prevent an episode.

I. Compositions

The compositions described here for mood stabilization may include anysuitable active agent in any pharmaceutically acceptable form. Forexample, the compositions may include any pharmaceutically acceptablesalts, prodrugs, racemic mixtures, conformational and/or opticalisomers, crystalline polymorphs and isotopic variants of the activeagents. The compositions may also be configured to have any suitableform, e.g., solid, semi-solid, or liquid. The compositions may also beprovided in unit dose form. In general, the compositions may include apartial opioid receptor agonist, e.g., a kappa-receptor agonist or akappa-receptor antagonist, and one or more additional active agents. Thecompositions may also be configured to include any suitable type ofrelease kinetics. For instance, the compositions may be configured torelease the partial opioid agonist, or one or more active agents in acontrolled release, delayed release, sustained release, immediaterelease, pulsatile, or continuous manner.

Partial Opioid Agonists

The compositions described here may include any suitable partial opioidagonist. The partial opioid agonists will generally be compounds havingsome agonist activity at opioid receptors. However, because they areweak agonists, they may also function as opioid receptor antagonists.Partial opioid agonists that may be useful here include buprenorphine,thienorphine, pentazocine, propiram, lofexidine, nalorphine, butorphanoland oxilorphan. Partial opioid agonists are also generally reviewed inChapter 21, section III of Goodman and Gilman's The PharmacologicalBasis of Therapeutics, supra, which is incorporated herein by reference.The partial opioid agonist may be a kappa opioid, i.e., a compoundhaving activity at the kappa (κ) opioid receptor. In one variation, thekappa opioid is a kappa receptor agonist. In another variation, thekappa opioid is a kappa receptor antagonist, e.g., buprenorphine.

Buprenorphine is 17-(cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,5-epoxy-18, 19-dihydro-3-hydroxy-6-methoxy-α-methyl-6,14-ethenomorphinan-7-methanol. Buprenorphine is manufactured and sold asbuprenorphine HCl by Reckitt Benckiser Pharmaceuticals (Richmond, Va.,sold as Buprenex (injectable; analgesic); Subutex (sublingual tablets;opioid addiction)). Buprenorphine is also manufactured and sold asSuboxone, a combination of buprenorphine HCl and naloxone HCl dehydratein a ratio of 4:1. Suboxone, like Subutex, is generally used in treatingopioid addiction and as an analgesic.

Buprenorphine is usually administered intravenously and sublingually. Asan analgesic, buprenorphine may be administered intravenously inrelatively low doses, e.g., 0.3-0.6 mg/injection. In treating opioidaddiction, buprenorphine (e.g., alone or in combination with naloxone)may be administered sublingually in doses upwards of from about 0.5mg-32 mg/day, for example, about 0.5, 1.0 2.0, 4.0, 8.0, 24, or 32mg/day. An effectiveness plateau may be reached at about 32 mg/day.Higher doses for treating opioid addiction may be required as a resultof opioid experience and therefore tolerance of addicted individuals.Here administration of buprenorphine by other modes are alsocontemplated.

In another variation, kappa opioids other than buprenorphine areemployed. For example, kappa receptor agonists and antagonists may beused. Suitable kappa receptor agonists include without limitation,butorphanol, BRL-52537, cyclazocine, enadoline, GR-89696, HZ-2,ICI-204,448, ketazocine, LPK-26(2-(3,4-Dichlorophenyl)-N-methyl-N-[(1S)-1-(2-isopropyl)-2-(1-(3-pyrrolinyl))ethyl]acetamide),nalbuphine, pentazocine, salvinorin A, spiradoline, tifluadom, U-50488,U-62066, U-69593, and combinations thereof. Exemplary kappa receptorantagonists for use in the compositions include without limitation,5′-guanidinonaltrindole, norbinaltorphimine, JDTic, and combinationsthereof.

Other Active Agents

In some variations, buprenorphine is administered in combination with anopioid antagonist. Suitable opioid antagonists that may be used withoutlimitation include natrexone and naloxone. Naltrexone can beadministered intravenously in doses of 0.2 mg-0.6 mg; subcutaneously 0.8mg; and intramuscularly 380 mg/week. Naltrexone can also be administeredorally or sublingually in doses of about 0.25 mg to about 8.0 mg, forexample, about 1.0 mg, 2.0 mg, 4.0 mg or 8.0 mg. Naloxone is availablefor intravenous, intramuscular or subcutaneous administration, inconcentrations from about 0.4 mg/mL to 1.0 mg/mL. In some variations,the opioid antagonist is provided with the partial opioid agonist, e.g.,buprenorphine, in a single dosage form.

In some variations, the kappa receptor antagonist, e.g., buprenorphine,is administered in combination with a mood stabilizer. Mood stabilizersfor use here include without limitation, lithium, aripiprazole(Abilify), olanzapine (Zyprexa), risperidone (Risperidal), quietiapine(Seroquel), and ziprasidone (Geodon). Therapeutic doses of lithium maybe about 300-1800 mg/day, for example, about 900-1200 mg/day.Specifically, lithium doses of about 300 mg, about 600 mg, or about 900mg per day may be useful. Therapeutic doses of ziprasidone may be about20-160 mg/day, for example, about 80-160 mg/day. Specifially,ziprasidone doses of about 40 mg, about 80 mg, or about 120 mg per daymay be useful. The therapeutic doses of aripiprazole may be about 1-30mg/day, for example, about 5-20 mg/day or about 10-15 mg/day.Specifically, aripriprazole doses may be about 2.0 mg, about 10 mg, orabout 15 mg per day.

In some variations, the partial opioid agonist, e.g., buprenorphine, maybe administered in combination with an antipsychotic agent. Theantipsychotic agents may be any class of antipsychotic, e.g., it may bea typical or atypical antipsychotic. Some antipsychotic agents may havesedative effects on the patient, and facilitate sleep. For instance,phenothiazines, thioxanthenes, and other heterocyclic compounds can allbe administered in combination with buprenorphine.

Phenothiazines that may be used include without limitation:chloropromazine hydrochloride, mesoridazine hydrochloride, thioridazinehydrochloride (Mellaril), fluphenazine hydrochloride (Prolixin),fluphenazine enanthate, fluphenazine decanoate, perphenazine,trifluoperazine hydrochloride (Stelazine), and combinations thereof.Other unlisted phenothiazine antipsychotics and analogs thereof can alsobe used.

Phenothiazines possessing relatively high sedative effect includewithout limitation: chlorpromazine hydrochloride (Largactil, Thorazine),mesoridazine hydrochloride, and thioridazine hydrochloride. In relationto these, perphenazine possesses a somewhat lower sedative effect.

Therapeutic doses for chlorpromazine hydrochloride may be about 30-2000mg/day, for example, about 200-800 mg/day. Therapeutic doses formesoridazine hydrochloride are about 30-400 mg/day, for example, about75-300 mg/day. Therapeutic doses for thioridazine hydrochloride areabout 20-800 mg/day, for example, about 15-600 mg/day. Perphenazine isadministered in a therapeutic dose range of about 4-64 mg/day, forexample, about 8-32 mg/day.

Thioxanthenes for use in the present invention include chloroprothixene,thiothixene hydrochloride (Navane), clopenthixol, cis-flupentixol, andpitflutixol. Other unlisted thioxanthene antipsychotics and analogsthereof can also be used.

Chloroprothixene is administered in a therapeutic dose range of about30-600 mg/day, for example, about 50-400 mg/day. Chloroprothixenepossesses moderately high sedative effects.

Other antipsychotic compounds, including other heterocyclicantipsychotic compounds for use herein may include without limitation:abripiprazole, arisulpride, clozapine, quetiapine fumarate, haloperidol,loxapine succinate (Loxapac, Loxitane), clothiapine, metiapine,zotepine, molindone hydrochloride, olanzapine, paliperidone, pimozide,prochlorperazine (Compazine, Buccastem, Stemetil or Phenotil)risperidone, trifluoroperazine, zuclopenthixol (Clopixol), andcombinations thereof. Other unlisted antipsychotics and analogs thereofcan also be used.

When olanzapine is used, it may be provided in a dose of about 5.0 mg,about 10 mg, or about 15 mg, or combinations thereof. When paliperidoneis provided, it may be provided in a dose of about 1.5 mg, about 3.0 mg,about 6.0 mg, or about 12 mg, or combinations thereof. With respect toquietiapine, it may be provided in a dose of about 50 mg, 100 mg, 300mg, or combinations thereof. When risperidone is used, it may beprovided in a dose of about 0.25 mg, about 0.5 mg, about 1.0 mg, about2.0 mg, about 3.0 mg, about 4.0 mg, or combinations thereof. Whenarisulpride is used, it may be provided in a dose of about 50 mg, about200 mg, or combinations thereof (between about 400-800 mg/day). Whentrifluoroperazine is used, it may be provided in doses of about 1.0 mg,2.0 mg, 5.0 mg, 10 mg, or combinations thereof.

In some variations, buprenorphine is administered in combination withziprasidone (Geodon). Ziprasidone can be administered in a therapeuticdose range of about 20-160 mg/day, for example, about 80-160 mg/day.Ziprasidone may be a favorable antipsychotic because it is hepaticallymetabolized by aldehyde oxidase. Only minor metabolism occurs via CYP3A4so there is a decreased likelihood of interactions from medications thatinduce or inhibit this enzyme (e.g., buprenorphine). Also, compared toother atypical antipsychotics, namely olanzapine, ziprasidone has abenign metabolic side effect profile with less likelihood ofmedication-induced weight gain, dyslipidemia, and insulin resistanceleading to diabetes. Because the prevalence of the metabolic syndromeand obesity in patients with bipolar disorder is even higher than thealready very high prevalence that has been estimated for the U.S.general population, the use of drugs which are metabolically neutral maytherefore be beneficial.

In some variations, buprenorphine is administered in combination witharipiprazole (Abilify). Aripiprazole can be administered in atherapeutic dose range of about 1-30 mg/day, for example, about 5-20mg/day or about 10-15 mg/day. Aripiprazole is another favorableantipsychotic because, similar to ziprasidone, it has a benign metabolicside effect profile.

In some variations, buprenorphine is administered in combination withquetiapine fumurate (Seroquel). Quetiapine fumurate can be administeredin a therapeutic dose range of about 50-750 mg/day, for example, about300-500 mg/day.

Clozapine can be administered in a therapeutic dose range of about12.5-900 mg/day, for example, about 150-450 mg/day. Aripiprazole can beadministered in a therapeutic dose range of 1-30 mg/day, for example,about 5-20 mg/day or about 10-15 mg/day. Clozapine and quetiapinefumarate exert moderately high sedative effects. Aripriprazole andziprasidone possess relatively low sedative effects.

In other variations, the partial opioid agonist, e.g., buprenorphine, isadministered in combination with an antiepileptic or an anticonvulsant.Exemplified antiepileptic agents include topiramate, zonisamide and thelike. Anticonvulsant agents may have sedative effects on the patient,and facilitate sleep. Anticonvulsants or antiepileptics for use hereinalong with their therapeutic doses include without limitation thefollowing classes of compounds: barbiturates (e.g., phenobarbitol(150-300 mg/day) and mephobarbitol), hydantoins (e.g., phenytoin(300-1000 mg/day)), iminostilbenes (e.g., carbamazepine (400-1600mg/day) and oxcarbazepine (450-2400mg/day)), and succinimides (e.g.,ethosuximide (250-2000 mg/day)). Other useful anti-convulsants/epilepticcompounds include: gabapentin (300-3600 mg/day), topiramate (50-1600mg/day), tiagabine (4-56 mg/day), levetiracetam (1000-3600 mg/day),felbamate (1200-3600 mg/day), zonisamide (100-600 mg/day), and valproicacid (10-100 mg/kg/day). Divalproex, lamotrigine, and oxacarbazine mayalso be used. Divalproex may be provided in doses of about 1000 mg,about 1500 mg, or about 2000 mg, or combinations thereof. Lamotriginemay be provided in doses or about 50 mg, about 100 mg, about 200mg, orcombinations thereof.

Drowsiness is a side effect of the barbiturates, as a class, andgabapentin, topiramate, ethosuximide, zonisamide, tiagabine. A sideeffect of carbamazepine, after long term treatment, may be drowsiness.

In some variations, the partial opioid agonist, e.g., buprenorphine, isadministered in combination with muscle relaxant. Muscle relaxants foruse in the present invention include: carisoprodol (1000-1400 mg/day),meprobamate (200-2400 mg./day), baclofen (15-80 mg/day), and tizanidine(4-36 mg/day).

In some variations, the partial opioid agonist, e.g., buprenorphine, isadministered in combination with ziprasidone (Geodon) and carisoprodol.

In some variations, the partial opioid agonist is administered incombination with an agent that potentiates its pharmacological effect,for example, an agent that competes with the P-450 enzymes thatmetabolizes the partial opioid agonist.

P-450 CYP3A4 or CYP2D6 Inhibitors (Buprenorphine Potentiators)

Buprenorphine is primarily metabolized by the cytochrome P450 enzymesCYP3A4 and CYP2D6. Therefore, administering buprenorphine in combinationwith an inhibitor of CYP3A4 and or CYP2D6 may potentiate thepharmacological effect of buprenorphine (e.g., by enhancingbioavailability). Combined administration of an inhibitor of CYP3A4and/or CYP2D6 with buprenorphine (either as separate dosage forms or ina single dosage form) may allow for administration of fewertherapeutically effective doses of buprenorphine and/or foradministration of subtherapeutic doses of buprenorphine.

In some variations, buprenorphine is administered in combination with orco-formulated with a CYP3A4 inhibitor as a second active agent.Exemplary CYP3A4 inhibitors include, without limitation, amiodarone,cannabinoids (e.g., dronabinol, nabilone, and Sativex), cimetidine,clarithromycin, delavirdine, erythromycin, fluconazole, indinavir,itraconazole, ketoconazole, metronidazole, miconazole, nefazadone,nelfinavir, nicardipine, norfloxacin, omeprozol, quinine, ritonavir,saquinavir, verapamil, zafirlukast and zileuton.

In some variations, buprenorphine is administered with a 2D6 inhibitor,e.g., cimetidine (Zantac). In some variations, the cimetidine isadministered at doses above 200 mg, for example, about 300 mg, 400 mg,600 mg or 800 mg. In other variations, buprenorphine is administeredwith a CB1 and CB2 agonist (e.g., Cannabinor and KN38-7271) or a CB1antagonist (e.g., Taranabant, Otenabant, Ibibipinabant, Surinabant, andDrinabant).

In other variations, buprenorphine is administered in combination withor co-formulated with a CYP2D6 inhibitor as a second active agent.Exemplary CYP2D6 inhibitors include, without limitation, quinidine,terbinafine, celecoxib, chloipheniramine, chlorpromazine, clemastine,clomipramine, cocaine, amiodarone, diphenhydramine, doxorubicin,goldenseal, halofantrine, histamine H1 receptor antagonists,hydroxyzine, levomepromazine, metoclopramide, mibefradil, midodrine,moclobemide, perphenazine, ranitidine, red-haloperidol, ritonavir,ticlopidine, and tripelennamine.

The CYP3A4 and/or CYP2D6 inhibitors are administered at theirrecommended or smaller doses for their approved uses. See, e.g., Goodmanand Gilman's, supra, Physician's Desk Reference, supra, and the FDAOrange Book.

Sugar

It has been reported that glucose and sucrose ingestion inducesproduction of endogenous opioids, which may alleviate opioid withdrawalsymptoms. See, e.g., Kracke, et al., Anesth Analg (2005) 101:64-8;Gharavi, et al., Pediatr Int (2007) 49:652; Jain, et al., Brain ResBull. (2004) 64:319-22; and Calantuoni, et al., Obesity Res (2002)10:478. Glucose administration can also alleviate opioid-induced memoryloss. See, e.g., Ragozzino, et al., Brain Res (1994) 655:77-82;Ragozzino, et al., J Neurosci (1998) 18:1595-1601; and Talley, et al.,Neurobiol Learn Mem (1999) 71:62-79. Sugars are also useful for thetransdermal delivery of opioids. See, e.g., U.S. Pat. No. 4,956,171 andPCT Publ. No. WO98/54196.

Accordingly, in some variations, the partial opioid agonist, e.g.,buprenorphine, is administered in combination with glucose or sucrose.The sugar can be in a solid or liquid form, as desired. For example, thepartial opioid agonist, e.g., buprenorphine, is co-administered with aconcentrated glucose or sucrose solution, or formulated with glucose orsucrose in sufficient amounts to induce induction of endogenous opioidsand/or to delay or alleviate withdrawal symptoms. In some variations,glucose is co-administered at a concentration of about 100 mg/kg. Insome variations, sucrose is co-administered in a solution containing atleast about 20% sucrose, for example, about 25%, 30%, 35% sucrosesolution.

Supplements/Additional Agents

In some variations, the partial opioid agonist, e.g., buprenorphine, isadministered in combination with one or more supplements. Thesupplements may, for example, be used to treat a comorbid condition,counteract any undesirable side effects of the partial opioid agonist orany other co-administered pharmacological agent, or counter nutritionaldeficiencies in the subject being treated.

In some variations, the supplement counteracts the side effect ofconstipation. For example, the partial opioid agonist can beco-administered or formulated with fiber or a bulking agent (e.g.,psyllium, inulin), a stool softener or a laxative.

In other variations, the supplement is used to counteract extrapyrimidalside-effects. Here the supplement may include an antihistamine, ananticholinergic, or combinations thereof. Exemplary antihistaminesinclude without limitation, certrizine, diphenydramine, fenofexadine,loratidine, and combinations thereof.

In some variations, the supplement counteracts a nutritional deficiency.For example, the partial opioid agonist can be co-administered orformulated with one or more B vitamins, e.g., thiamin (B-1), riboflavin(B-2), niacin, pyridoxine (B-6), folic acid, cobalamin (B-12), biotin,and/or pantothenic acid. In some variations, one or more of vitamins A,C, D, E or K is co-administered with the partial opioid agonist. In somevariations, the partial opioid agonist is co-administered orco-formulated with one or more of calcium, iron, zinc, selenium,magnesium, manganese, copper and/or chromium. In some variations, thepartial opioid agonist is co-administered or co-formulated with anantioxidant, e.g., lycopene, acetylcysteine.

In other variations, the supplement or additional agent is used to treata comorbid condition. For example, the comorbid condition may bediabetes, obesity, or fibromyalgia. When diabetes is the comorbidcondition, the additional agent may be metformin. When the comorbidcondition is obesity, the additional agent may be metformin, topiramate,or combinations thereof. When the comorbid condition is fibromyalgia,the additional agent may be carisoprodol, colchicine, cyclobenzaprine,duloxetine, gabapentin, guafenisin, interferon, methocarbamol,pregabalin, probenecid, sulfinpyrazone, vitamin B 12, or combinationsthereof.

In some variations, the partial opioid agonist is administered incombination with or co-formulated with an opioid abuse deterrent agent,for example, an opioid antagonist.

Abuse deterrent agents find use that are healthful or benign whenco-administered at low concentrations, but produce undesirable orunpleasant side effects when co-administered at higher concentrations,for example, when a patient attempts to administer more than theprescribed dose of the partial opioid agonist. For example, niacin atlow doses (e.g., 10-50 mg) serves as a B vitamin supplement, but athigher doses will cause flushing. Acetylcysteine at low doses serves asan antioxidant, but at higher doses, the sulfur content has a noticeableand unpleasant smell. Glucose or sucrose administered at lower doseswill potentiate the effects of the partial opioid agonist, as discussedabove, but at higher doses will cause unpleasant side effects, forexample, due to high levels of insulin release.

Other sulfur-containing compounds find use as abuse deterrent agents.Nociceptive agents also find use as abuse deterrent agents, for example,capsaicin, chili pepper and other hot pepper extracts.

It may be important here to mention that in the methods, compositions,and kits described here, some agents may not contemplated forcombination with the opioid agonists. In some variations, the partialopioid agonist, e.g., buprenorphine, may be administered to a subjectwithout administering in combination an antidepressant. It isunfavorable to administer antidepressants to patients who are subject tomanic or hypomanic episodes, including individuals with bipolardisorder, because all antidepressants can precipitate or exacerbatemania or hypomania.

Antidepressant compounds excluded include, for example, atypicalantidepressants (e.g., atomoxetine, bupropion, duloxetine, mirtazapine,nefazodone and trazodone), tricyclic antidepressants (e.g., amineptine,amitriptyline, clomipramine, desipramine, doxepin, dothiepin,imipramine, nortriptyline, protriptyline, trimipramine, lofepramine,amoxapine and the muscle relaxant cyclobenzaprine), monoamine oxidaseinhibitors (e.g., phenelzine, tranylcypromine, and selegiline),norepinephrine reuptake inhibitors (e.g, amitriptyline, clomipramine,doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline,nortriptyline and protri_(p)t_(y)line), serotonin-norepinephrinereuptake inhibitors (e.g., milnacipran, mirtazapine, duloxetine,venlafaxine and sibutramine), norepinephrine-dopamine reuptakeinhibitors (e.g., amineptine, modafinil and bupropion), and selectiveserotonin reuptake inhibitors (e.g, citalopram, escitalopram,fluoxetine, fluvoxamine, paroxetine, and sertraline).

In other variations, the partial opioid agonist may be administered to asubject without administering in combination a benzodiazepine.Benzodiazepines excluded include, for example, alprazolam (Xanax),valium, diazepam, temazepam (Restoril), lorazepam, chlordiazepoxide(Librium) and clonazepam (Klonopin).

Dosage Forms

Also described here are pharmaceutical compositions comprising a partialopioid agonist, a second active agent, and/or an additional/supplementalagent. The compositions may include a mixture of an effective amount ofa partial opioid agonist (e.g., buprenorphine) and one or more opioidantagonist(s) and/or one or more antipsychotic(s) and/or one or moreanticonvulsant(s) and/or one or more antiepileptic(s) and/or one or moremuscle relaxant(s) agents and/or one or more mood stabilizer(s). Thepartial opioid agonist and/or the combined pharmacological agents, i.e.,opioid antagonist(s), antipsychotic(s), anticonvulsant(s),antiepileptic(s), muscle relaxant(s), may be included in therapeutic orsubtherapeutic doses. In some variations, the compositions comprise oneor both pharmacological agents in subtherapeutic doses. The compositionscan be co-formulated with one or more opioid potentiators, supplementsand/or opioid deterrent agents, as discussed above.

In some variations, the pharmaceutical compositions comprise one or moreopioid antagonists. In one variation, the pharmaceutical compositioncomprises naltrexone. In another variation, the pharmaceuticalcomposition comprises naloxone.

In some variations, the pharmaceutical compositions comprise one or moreantipsychotics. The antipsychotic may include without limitation, aphenothiazine, a thioxanthene, or other heterocyclic compounds andprodrugs thereof. In one variation, the pharmaceutical compositioncomprises one or more antipsychotics selected from the group ofquetiapine, aripiprazole, clozapine and ziprasidone. Additionalantipsychotics can find use, for example, those described herein. In onevariation, the pharmaceutical composition comprises subtherapeuticamounts of antipsychotic(s).

In some variations, the pharmaceutical compositions comprise one or moreanticonvulsants(s)/antiepileptic(s). The anticonvulsant/antiepilepticcan be selected from barbiturates, hydantoins, iminostilbenes,succinimides, valproic acid and prodrugs thereof. Additionalanticonvulsants can find use, for example, those described herein. Inone variation, the pharmaceutical composition comprises one or moreanticonvulsive(s)/antiepileptic(s) in subtherapeutic amounts.

In some variations, the pharmaceutical compositions comprise one or moremood stabilizer(s) and the prodrugs thereof. In one variation, thepharmaceutical composition comprises one or more mood stabilizerselected from the group of lithium and ziprasidone. Additional moodstabilizer can find use, for example, those described herein. In onevariation, the pharmaceutical composition comprises one or more moodstabilizers in a subtherapeutic amount.

In some variations, the pharmaceutical compositions comprise one or moremuscle relaxant(s) and the prodrugs thereof. In one variation, thepharmaceutical composition comprises the muscle relaxant carisoprodol.Additional muscle relaxants can find use, for example, those describedherein. In one variation, the pharmaceutical composition comprises oneor more muscle relaxant(s) in a subtherapeutic amount.

A combination of partial opioid agonist (e.g., buprenorphine) and/or oneor more opioid antagonist(s) and/or one or more antipsychotic(s) and/orone or more anticonvulsant(s) and/or one or more antiepileptic(s) and/orone or more muscle relaxant(s) and/or one or more mood stabilizer(s)agents can be administered to a subject, e.g., a human patient, adomestic animal such as a dog or a cat, independently or together in theform of a pharmaceutically acceptable salts, or in the form of apharmaceutical composition where the compounds are mixed with suitablecarriers or excipient(s) in an effective amount.

A combination of partial opioid agonist (e.g., buprenorphine) and/or oneor more opioid antagonists and/or one or more antipsychotic(s) and/orone or more anticonvulsant(s) and/or one or more antiepileptic(s) and/orone or more muscle relaxant(s) and/or one or more mood stabilizer(s)agents of this invention can be incorporated into a variety offormulations for therapeutic administration. More particularly, acombination of the present invention can be formulated intopharmaceutical compositions, together or separately, by formulation withappropriate pharmaceutically acceptable carriers or diluents, and can beformulated into preparations in solid, semi-solid, liquid or gaseousforms such as tablets, capsules, pills, powders, granules, dragees,gels, slurries, ointments, solutions, suppositories, patches, films,injections, inhalants, and aerosols.

Suitable formulations for use in the present invention are found in, forexample, in Remington: The Science and Practice of Pharmacy, 21^(st)Ed., 2005; Martindale: The Complete Drug Reference, Sweetman, 2005,London: Pharmaceutical Press; Niazi, Handbook of PharmaceuticalManufacturing Formulations, 2004, CRC Press; and Gibson, PharmaceuticalPreformulation and Formulation: A Practical Guide from Candidate DrugSelection to Commercial Dosage Form, 2001, Interpharm Press, which arehereby incorporated by reference herein. The pharmaceutical compositionsdescribed herein can be manufactured in a manner that is known to thoseof skill in the art, i.e., by means of conventional mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating,entrapping or lyophilizing processes. The following methods andexcipients are merely exemplary and are in no way limiting.

The pharmaceutical preparations of the present invention can be preparedfor delivery in a sustained-release, controlled release,extended-release, timed-release or delayed-release formulation, forexample, in semi-permeable matrices of solid hydrophobic polymerscontaining the effective agent(s). Various types of sustained-releasematerials have been established and are well known by those of skill inthe art. Current extended-release formulations include film-coatedtablets, multiparticulate or pellet systems, matrix technologies usinghydrophilic or lipophilic materials and wax-based tablets withpore-forming excipients (see, for example, Huang, et. al., Drug Dev. IndPharm. 29:79 (2003); Pearnchob, et. al., Drug Dev. Ind Pharm. 29:925(2003); Maggi, et. al., Eur. J. Pharm. Biopharm. 55:99 (2003);Khanvilker, et. al., Drug Dev. Ind. Pharm. 228:601 (2002); and Schmidt,et. al., Int. J. Pharm. 216:9 (2001). Sustained-release delivery systemscan, depending on their design, release the compounds over the course ofhours or days, for instance, over 4, 6, 8, 10, 12, 16, 20, 24 hours ormore Sustained release formulations can be prepared usingnaturally-occurring or synthetic polymers, for instance, polymeric vinylpyrrolidones, such as polyvinyl pyrrolidine (PVP); carboxyvinylhydrophilic polymers; hydrophobic and/or hydrophilic hydrocolloids, suchas methylcellose, ethylcellulaose, hydroxypropylcellulose, andhydroxypropylmethylcellulose; and carboxypolmethylene.

The sustained or extended-release formulations can also be preparedusing natural ingredients, such as minerals, including titanium dioxide,silicon dioxide, zinc oxide, and clay (see, U.S. Pat. No. 6,638,521,herein incorporated by reference). Exemplified extended releaseformulations that can be used in delivering a combination of partialopioid agonist (e.g., buprenorphine) and/or one or more opioidantagonist(s) and/or one or more antipsychotic(s) and/or one or moreanticonvulsant(s) and/or one or more antiepileptic(s) and/or one or moremuscle relaxant(s) and/or one or more mood stabilizer(s) agents of thepresent invention include those described in U.S. Pat. Nos. 6,635,680;6,624,200; 6,613,361; 6,613,358, 6,596,308; 6,589,563; 6,562,375;6,548,084; 6,541,020; 6,537,579; 6,528,080 and 6,524,621, each of whichis hereby incorporated herein by reference. Controlled releaseformulations of particular interest include those described in U.S. Pat.Nos. 6,607,751; 6,599,529; 6,569,463; 6,565,883; 6,482,440; 6,403,597;6,319,919; 6,150,354; 6,080,736; 5,672,356; 5,472,704; 5,445,829;5,312,817 and 5,296,483, each of which is hereby incorporated herein byreference. Those skilled in the art will readily recognize otherapplicable sustained release formulations.

For oral administration, a combination of partial opioid agonist (e.g.,buprenorphine) and/or one or more opioid antagonist(s) and/or one ormore antipsychotic(s) and/or one or more antipsychotic(s) and/or one ormore anticonvulsant(s) and/or one or more antiepileptic(s) and/or one ormore muscle relaxant(s) and/or one or more mood stabilizer(s) agents canbe formulated readily by combining with pharmaceutically acceptablecarriers that are well known in the art. Such carriers enable thecompounds to be formulated as tablets, pills, dragees, capsules,emulsions, lipophilic and hydrophilic suspensions, liquids, gels,syrups, slurries, suspensions and the like, for oral ingestion by apatient to be treated. Pharmaceutical preparations for oral use can beobtained by mixing the compounds with a solid excipient, optionallygrinding a resulting mixture, and processing the mixture of granules,after adding suitable auxiliaries, if desired, to obtain tablets ordragee cores. Suitable excipients are, in particular, fillers such assugars, including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents can beadded, such as a cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds can be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers can be added. All formulations fororal administration should be in dosages suitable for suchadministration.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions can be used, which can optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

The compounds can be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Forinjection, a combination of partial opioid agonist (e.g., buprenorphine)and one or more mood stabilizers, one or more antipsychotics and/or oneor more anticonvulsants and/or one or more antiepileptics and/or one ormore muscle relaxant(s) agents can be formulated into preparations bydissolving, suspending or emulsifying them in an aqueous or nonaqueoussolvent, such as vegetable or other similar oils, synthetic aliphaticacid glycerides, esters of higher aliphatic acids or propylene glycol;and if desired, with conventional additives such as solubilizers,isotonic agents, suspending agents, emulsifying agents, stabilizers andpreservatives. Preferably, a combination of the invention can beformulated in aqueous solutions, preferably in physiologicallycompatible buffers such as Hanks's solution, Ringer's solution, orphysiological saline buffer. Formulations for injection can be presentedin unit dosage form, e.g., in ampules or in multi-dose containers, withan added preservative. The compositions can take such forms assuspensions, solutions or emulsions in oily or aqueous vehicles, and cancontain formulatory agents such as suspending, stabilizing and/ordispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds can be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions can contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension can also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient can be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.For topical administration, the agents are formulated into ointments,creams, salves, powders and gels. In one variation, the transdermaldelivery agent can be DMSO. Transdermal delivery systems can include,e.g., patches. For transmucosal administration, penetrants appropriateto the barrier to be permeated are used in the formulation. Suchpenetrants are generally known in the art. Exemplified transdermaldelivery formulations that can find use in the present invention includethose described in U.S. Pat. Nos. 6,589,549; 6,544,548; 6,517,864;6,512,010; 6,465,006; 6,379,696; 6,312,717 and 6,310,177, each of whichare hereby incorporated herein by reference.

For buccal administration, the compositions can take the form of tabletsor lozenges formulated in a conventional manner.

In addition to the formulations described previously, a combination ofpartial opioid agonist (e.g., buprenorphine) and/or opioid antagonist(s)and/or one or more antipsychotics and/or one or more anticonvulsantsand/or one or more antiepileptics and/or one or more muscle relaxant(s)and/or one or more mood stabilizer(s) agents of the present inventioncan also be formulated as a depot preparation. Such long actingformulations can be administered by implantation (for examplesubcutaneously or intramuscularly), or by needle-free injection. Thus,for example, the compounds can be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

The pharmaceutical compositions also can comprise suitable solid or gelphase carriers or excipients. Examples of such carriers or excipientsinclude but are not limited to calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and polymerssuch as polyethylene glycols.

II. Kits

The compositions described here may be provided in a kit. Kits fortreating mania associated with opioid withdrawal may include a pluralityof buprenorphine dosage forms and instructions for administering thedosage forms according to a predetermined dosage regimen. Here thepredetermined dosing regimen may include administering a firstbuprenorphine dose and at least one additional buprenorphine dose thatis less than the first dose. The predetermined dosing regimen mayprovide that the first dose be administered in the morning, e.g., at 6am or between about 6 am and 9 am, and the at least one additional doseadministered in the afternoon, e.g., at 12 pm (noon) or between about 12pm and 3 pm, evening, e.g., at 6 pm or between about 6 pm and 9 pm, orlate evening, e.g., at 12 am (midnight).

The aforementioned kits may include a housing configured to organize thedosage forms according to the predetermined dosing regimen. For example,the housing may be configured to organize the plurality of dosage formsinto morning dosage forms and evening dosage forms. In some variations,the housing may be configured to organize the plurality of buprenorphinedosage forms according to a rapidly or a gradually decreasing dosingregimen. In yet further variations, the housing may be configured toorganize the buprenorphine dosage forms according to the day of the weekto be taken.

The kits may also include a second dosage form having one or more secondactive agents. The second active agent may also help to stabilize themood of the patient. Exemplary second active agents include withoutlimitation, aripriprazole, arisulpride, olanzapine, paliperidone,quetiapine, risperidone, ziprasidone, and combinations thereof. The kitmay further include additional dosage forms that include one or moreadditional agents for treating a comorbid condition. For example, anantihistamine may be useful to include when the comorbid condition is asleep disorder. Dosage forms that include other active agents (e.g., totreat comorbidities) or second active agents (e.g., for moodstabilization) may be organized in the housing similar to theorganization provided for the buprenophine dosage forms, as describedabove.

Kits for treating the symptom of racing thoughts in bipolar disorder mayinclude a plurality of buprenorphine dosage forms, at least one seconddosage form comprising a second active agent that helps to stabilizemood, e.g., an atypical antipsychotic agent, and instructions for takingthe dosage forms according to a predetermined dosing regimen. Dosageforms including an opioid antagonist such as naloxone may also beincluded. In some variations, dosage forms having a supplemental oradditional agent for treating a comorbid condition, side-effect ofsecond agent, and/or other symptoms of bipolar disorder may be providedin the kits.

These kits may also further include a housing configured to organize thedosage forms according to the predetermined dosing regimen. For example,the housing may be configured to organize the plurality of dosage formsinto morning dosage forms and evening dosage forms. In some variations,the housing may be configured to organize the plurality of dosage formsaccording to a rapidly or a gradually decreasing dosing regimen. In yetfurther variations, the housing may be configured to organize the dosageforms according to the day of the week to be taken. The kits may also betailored to treat particular bipolar conditions or subtypes. Forexample, the kits may be tailored to treat bipolar I disorder, bipolarII disorder, mixed bipolar disorders, rapidly-cycling bipolar disorder,acute mania, drug-induced mania, hypomania, cyclothymia, or combinationsthereof.

In some variations, the kits comprise a partial opioid agonist (e.g.,buprenorphine) and/or one or more opioid antagonist(s) and/or one ormore antipsychotic(s) and/or one or more anticonvulsant(s) and/or one ormore antiepileptic(s) and/or one or more muscle relaxant(s) and/or oneor more mood stabilizer(s) agents in separate formulations or dosageforms. In other variations, the kits comprise a partial opioid agonist(e.g., buprenorphine) and/or one or more opioid antagonist(s) and/or oneor more antipsychotic(s) and/or one or more anticonvulsant(s) and/or oneor more antiepileptic(s) and/or one or more muscle relaxant(s) and/orone or more mood stabilizer(s) agents within the same formulation ordosage form.

In further variations, the kits may provid the of partial opioid agonist(e.g., buprenorphine) and/or one or more opioid antagonist(s) and/or oneor more antipsychotic(s) and/or one or more anticonvulsant(s) and/or oneor more antiepileptic(s) and/or one or more muscle relaxant(s) and/orone or more mood stabilizer(s) agents independently in uniform dosageformulations throughout the course of treatment. In some variations, thekits provide the of partial opioid agonist (e.g., buprenorphine) and/orone or more opioid antagonist(s) and/or one or more antipsychotic(s)and/or one or more anticonvulsant(s) and/or one or more antiepileptic(s)and/or one or more muscle relaxant(s) and/or one or more moodstabilizer(s) agents independently in graduated dosages over the courseof treatment, either increasing or decreasing, according to therequirements of the subject or according to a predetermined dosingregimen.

In some variations, the kits comprise a partial opioid agonist,buprenorphine. In one variation, the kit comprises compositionscomprising a subtherapeutic amount of buprenorphine.

In some variations, the kits comprise compositions comprising one ormore opioid antagonist(s). In one variation, the opioid antagonist isnaloxone.

In other variations, the kits comprise dosage forms comprising one ormore antipsychotic(s). The antipsychotics can be selected from aphenothiazine, a thioxanthene, or other heterocyclic compounds. In onevariation, the kit comprises one or more antipsychotics selected fromthe group of quetiapine, aripiprazole, clozapine and ziprasidone. In onevariation, the kit comprises compositions comprising antipsychotic(s) ina subtherapeutic amount.

In one variation, the kit comprises one or more mood stabilizers. In onevariation, the kit comprises a mood stabilizer selected from the groupconsisting of lithium and ziprasidone. In one variation, the kitcomprises compositions comprising mood stabilizer(s) in a subtherapeuticamount.

In one variation, the kits comprise of anticonvulsant/antiepilepticagents. In some variations, the kit comprises one or moreanticonvulsants/antiepileptics that are barbiturates, hydantoins,imminostilbenes and/or succinimides. In one variation, the kit comprisessubtherapeutically effective amounts of anticonvulsant/antiepilepticagent(s).

In some variations, the kits comprise muscle relaxant(s). In somevariations, the kit comprises the muscle relaxant carisoprodol. In onevariation, the kit comprises compositions comprising muscle relaxant(s)in a subtherapeutic amount.

The kits may also comprising a housing configured to organize the dosageforms according to a predetermined dosing regimen. For example, thehousing may be configured to organize the plurality of dosage forms intomorning dosage forms and evening dosage forms. The housing may also beconfigured to organize the plurality of buprenorphine dosage formsaccording to a rapidly or a gradually decreasing dosing regimen.

III. Methods

The methods described here may find use in the treatment and preventionof mood disorders involving manic episodes. In particular, the methodsmay find use in the amelioration, inhibition, reduction and preventionof symptoms indicative of a manic episode or hypomanic episode, e.g.,racing thoughts, as described herein. Exemplified general categories ofdisorders treatable by the present methods and compositions include,without limitation, bipolar disorder, mania and manic episodes,hypomania, cyclothymia, and drug-induced mania, among others. Themethods promote and facilitate regular sleep patterns in individualssubject to manic or hypomanic epidodes. The methods may also treat orprevent manic or hypomanic episodes occurring in these disorders insubjects afflicted with concurrent substance addiction and/or withdrawalfrom substances of abuse.

For example, during opioid withdrawal, many adverse withdrawal symptomsmay occur. Physical manifestations often include sweating, nausea,chills, diarrhea, papillary dilation, piloerection, tachycardia,increased blood pressure, hypersensitivity to pain, stomach cramps, andmuscle cramps. Psychological manifestations of opioid withdrawal includedysphoria, restlessness, irritability, mania, anxiety, and depression.Due to the often severe nature of the withdrawal symptoms, individualswho are addicted to or dependent on opioids often choose to remainaddicted or dependent rather than seek treatment. This may presentsignificant inhibition to an individual being able to overcome his/heraddiction. The methods here address this need by providing methods forpreventing or inhibiting these withdrawal symptoms, especially maniatriggered experienced during opioid withdrawal. Therapeutic orsubtherapeutic amounts of buprenorphine may be administered to treat orprevent opioid withdrawal induced mania.

As previously stated, the treatment regimens may achieve moodstabilization by administering a partial opioid agonist, e.g.,buprenorphine, in a predetermined fashion. The amounts and frequency ofadministration of the partial opioid agonist will vary depending on suchfactors as the particular type of bipolar disorder diagnosed, associatedsymptoms and/or comorbidities, other medications being taken by thepatient, and previous history of opioid abuse. For example, when aplurality of buprenorphine doses are administered per day, the firstdose may be higher than any additional dose given. In some variations, amorning dose of buprenophine may be higher than a buprenorphine dosegiven in the evening or late evening. For example, a buprenophine doseadministered at 6 am may be higher than a buprenorphine dose given inthe evening, e.g., at 6 pm, or late evening., e.g., at 12 am (midnight).In some variations, the treatment regimens may include rapidlydecreasing the buprenorphine dose over the course of a day. In othervariations, a gradual decrease in the buprenorphine dose is employed(over a day). Exemplary (predetermined) dosing regimens are shown belowin Table 1.

TABLE 1 Exemplary Dosing of Buprenorphine For Treatment of ManiaAssociated With Opioid Withdrawal First Dose Additional Dose AdditionalDose (e.g., morning Additional Dose (e.g., evening (e.g., late eveningdose at 6 am) (e.g., 12 pm) dose at 6 pm) dose at 12 am) in mg in mg inmg in mg 32 0 0 0 24 0 0 0 24 4 2 1 16 0 0 0 16 8 0 0 16 8 4 0 16 8 4 216 4 2 1 8 8 0 0 8 4 4 0 8 4 2 1 4 0 0 0 4 4 4 0 4 2 1 0 4 2 1 0.5 2 0 00 2 2 2 0 2 2 1 0 2 2 1 0.5

In some variations, the treatment regimens may include rapidlydecreasing the buprenorphine dose over the course of a day. In othervariations, a gradual decrease in the buprenorphine dose is employed(over a day). The treatment regimens may be useful in treating maniaassociated with opioid withdrawal. As previously stated, the inventorsbelieve that when higher doses of buprenorphine are taken in theevening, it acts as a mood destabilizer and thus, kindles mania ormania-like symptoms in this patient population. In another variation,the treatment regimens may be beneficial in alleviating racing thoughtsduring the depressive phase of bipolar disorder.

In Table 1, certain doses of buprenorphine are shown as 0 mg. In theseinstances, a dosage form may be administered that includes a carrier,filler, second active agent, supplemental/additional agent, etc., but itwill lack buprenorphine. In other instances, no dosage form may beadministered.

When a second active agent is administered with buprenorphine (oranother partial opioid agonist), it may also be administered in arapidly or gradually increasing or decreasing manner throughout the day.In some variations, the second active agent is administered in anincreasing manner, i.e., the morning dose is lower than the evening orlate evening dose. In other variations, the dosing of the second activeagent and partial opioid agonist is inverse to one another.

Administered dosages for partial opioid agonists, e.g., buprenorphine,opioid antagonist(s), antipsychotic(s), mood stabilizer(s),anticonvulsant(s), antiepileptic(s), and muscle relaxant(s) are inaccordance with dosages and scheduling regimens practiced by those ofskill in the art. For example, buprenorphine may be administered dailyin doses of about 2 mg, about 4 mg, about 6 mg, about 8 mg, about 10 mg,about 12 mg, about14 mg, about 16 mg, about 18 mg, about 20 mg, about 22mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, or about 32 mg.In some variations, when a higher dose of buprenorphine is administered,a high dose of mood stabilizer is also administered. General guidancefor appropriate dosages of all pharmacological agents used in thepresent methods is provided in Goodman and Gilman's The PharmacologicalBasis of Therapeutics, 11^(th) Edition, 2006, supra, in a Physicians'Desk Reference (PDR), for example, in the 62n^(d) (2008) Ed., ThomsonPDR, and in the FDA Orange Book, which are hereby entirely incorporatedby reference herein. In the compositions and methods of the presentinvention, efficacious dosages of opioid partial agonist(s), opioidantagonist(s), antipsychotic(s), mood stabilizer(s), anticonvulsant(s),antiepileptic(s), and muscle relaxant(s) for practicing the presentinvention can be equal to or less than (e.g., about 25, 50, 75, or 100%)the dosages published for other indications. Combining an opioid partialagonist with a mood stabilizer, an antipsychotic, a mood stabilizer, ananticonvulsant, an antiepileptic or a muscle relaxant allows for bothpharmacological agents to be administered at subtherapeutic doses andelicit an efficacious effect in reducing or preventing the symptoms of amanic episode.

The appropriate dosage of partial opioid agonists (buprenorphine),opioid antagonist(s), antipsychotic(s), mood stabilizer(s),anticonvulsant(s), antiepileptic(s), and muscle relaxant agent(s) willvary according to several factors, including the chosen route ofadministration, the formulation of the composition, patient response,the severity of the condition, the subject's weight, and the judgment ofthe prescribing physician. The dosage can be increased or decreased overtime, as required by an individual patient. Usually, a patient initiallyis given a low dose, which is then increased to an efficacious dosagetolerable to the patient. Patients who have not before been exposed toopioids will require lower doses. Patients who have been exposed toopioids, or who have opioid dependence or addiction, will require higherdoses.

For the methods of the present invention, subtherapeutic dosages ofbuprenorphine are administered at doses that are about 25% or less of afull dose for the indicated purposes of buprenorphine. For example, inthe present methods buprenorphine is administered in amounts that areabout 25%, 20%, 15%, 10%, 5%, 2%, 1% or less than a full dose. Dosing ofbuprenorphine is known in the art and published in standard referencetexts commonly consulted by trained clinicians, including for example,Goodman and Gilman's The Pharmacological Basis of Therapeutics, 11thEdition, 2006, supra, in a Physicians' Desk Reference (PDR), forexample, in the 62nd (2008) Ed., Thomson PDR, and in the FDA OrangeBook. In treating opioid addiction, buprenorphine (e.g., alone or incombination with naloxone) typically is administered sublingually infull doses of from about 2-32 mg/day, for example, about 2, 4, 8, 16 or32 mg/day. In some embodiments, the subtherapeutic amounts ofbuprenorphine are administered sublingually, for example, in amountsthat are about 25% of a full dose or less, for example, about 20%, 15%,10%, 5%, 2% of a full dose. In some embodiments, the subtherapeuticamounts of buprenorphine are administered sublingually in doses of fromabout 0.4-8 mg/day, for example, about 0.4, 1, 2, 4 or 8 mg/day. In someembodiments, standard or full doses of sublingually formulatedbuprenorphine are administered orally (based on a 20% or ⅕bioavailability of the sublingual formulation when orally administered).

Generally, in practicing the present methods, effective amounts of oneor more partial opioid agonists are administered alone or in combinationwith and/or one or more opioid antagonist(s), and/or one or moreantipsychotic(s) and/or one or more anticonvulsant(s) and/or one or moreantiepileptic(s) and/or one or more muscle relaxant(s) and/or one ormore mood stabilizers. Co-administered pharmacological agents can beadministered together or separately, simultaneously or at differenttimes. When administered, the partial opioid agonist(s), alone or incombination with opioid antagonist(s), antipsychotic(s), moodstabilizer(s), muscle relaxant(s), and/or anticonvulsant(s)/antiepileptic(s) agents independently can be administered once, twice,three, four times daily or more or less often, as needed. In somevariations, the administered pharmacological agents are administeredonce daily. In some variations, the partial opioid agonist isadministered at a high dose, alone or in combination with anotheraforementioned pharmacological agent, in the morning, and then at alower dose in the evening, for example, before bedtime. This regimen maybe less likely to kindle mania and promote drowsiness and sleep. When amood stabilizer is also employed in the dosing regimen, it may bemonodosed, e.g., given before bedtime, or at a multiple times throughoutthe day.

For certain patients, the methods are carried out concurrentlyadministering the one or more partial opioid agonist and/or then one ormore opioid antagonist(s) and/or one or more antipsychotic(s) and/or oneor more anticonvulsant(s) and/or one or more antiepileptic(s) and/or oneor more muscle relaxant(s) and/or one or more mood stabilizer(s) fromthe initiation of treatment. For certain patients, the methods arecarried out by first administering the one or more partial opioidagonist(s), and then subsequently co-administering the and/or one ormore opioid antagonist and/or one or more antipsychotics and/or one ormore anticonvulsants and/or one or more antiepileptics and/or one ormore muscle relaxant(s) and/or one or more mood stabilizer.

Administration of the partial opioid agonist, for example,buprenorphine, alone or in combination with and/or one or more opioidantagonist and/or one or more antipsychotic(s) and/or one or moreanticonvulsant(s) and/or one or more antiepileptic(s) and/or one or moremuscle relaxant(s) and/or one or more mood stabilizer(s), can beachieved in various ways, including oral, buccal, parenteral,intravenous, intradermal, subcutaneous, intramuscular, transdermal,transmucosal, intranasal, etc., administration. Buprenorphine, or otherpartial opioid agonist, can be administered by the same or differentroute of administration when co-administered with one or more opioidantagonist(s) and/or one or more antipsychotic(s) and/or one or moreanticonvulsant(s) and/or one or more antiepileptic(s) and/or one or moremuscle relaxant(s) and/or one or more mood stabilizer(s).

In some variations, a partial opioid agonist, for example,buprenorphine, alone or in combination, can be administered in a localrather than systemic manner, for example, transdermally or via anotherroute in a depot or sustained release formulation. In some variations,the partial opioid agonist is administered orally. In some variations,the partial opioid agonist is administered sublingually.

EXAMPLES

The following examples are offered to illustrate the treatment regimens,compositions, and kits described herein.

Example 1

A 35 year old man presented with an addiction to Methadone. Patient wastearful, admitting to feeling depressed and was prone to paroxysms ofgrandiose and irritable behavior. He had been diagnosed with bipolardisease type I several months ago and was started on Seroquel. Eventhough he liked the effects of Seroquel on sleep promotion, he onlyremembered to take it intermittently and instead predominantly usedopioid drugs to self-treat prepsychotic and psychotic symptoms. With 8mg of Suboxone tid, his psychiatric symptoms largely resolved and hebegan taking the Seroquel regularly, resulting in maximum stabilizationof mood fluctuation 1 month later.

Example 2

A 35 year old female with a history of bipolar disease and oxycontin usepresented with hypomania as characterized by an expansive, elevatedmood, and rapid speech. She had been started on Lithium 300 mg tid butstopped it because she missed her “highs.” She was, however, complainingof severe “back pain” for which she wanted a narcotic. She was startedon 8 mg of Suboxone bid along with Geodon 40 mg bid and the patient hasremained compliant on her medications for over 3 months. On herfollow-up visits she demonstrates no manic or hypomanic symptoms.

Example 3

A 45 year old opioid addicted female with schizoaffective disorder andcompletely noncompliant with her oral psychiatric meds presented inflorid psychosis. 2 mg of Suboxone was administered sublingually and thepsychosis immediately resolved. Geodon and Lithium were restarted and incombination with psychotherapy, the patient has remained on hermedications (including Suboxone) and otherwise drug-free for over 6months.

Example 4

A 39 year old bipolar female presented with a history of regular crackcocaine use and high doses of intermittent opioids. Previous attempts atinitiating an atypical antipsychotic had failed. After starting onSeroquel and Suboxone, she has achieved full remission of symptoms andfull return to functioning.

Example 5

A 23 year old male presented with bipolar disorder and prescription drugaddiction. He had been unable to tolerate any mood stabilizers orpsychotropics. Shortly after starting on Suboxone, Lamictal was begunand the patient remained on therapy with considerable normalization ofhis mood.

Example 6

A 27 year old male presented with an opioid addiction and bipolardisorder. Although he formerly did not adhere regularly to hismedication regimen which included Seroquel and thorazine, once hestarted Suboxone he became very compliant and his psychiatric symptomshave abated considerably.

Example 7

A 47 year old female with a history of opioid addiction and bipolardisease presented with a mania and was started on lithium 300 mg tid,but stopped it due to intolerable side effects. She was started onSuboxone 8 mg bid and, although she states she does not notice a changefrom the Suboxone, her mood has normalized. Three months later shecontinues to do well.

Example 8

A woman presented with a manic episode immediately after her husband'sdeath due to a subdural hematoma after a car accident. The outburst ofmanic episode that emerges after the death of a close family member istermed bereavement mania in the literature. There was a history ofbipolar disorder in the patient which had been previously verywell-controlled by 1200mg of Lithium tid. The DSM IV criteria for manicepisode were met even though blood tests showed her lithium levels to bein therapeutic range. She was asking for narcotics to take away hernearly constant headache. She was started on Suboxone 8 mg tid and hermania subsided. A month later the Suboxone was stopped. There has beenno recurrence of mania for almost 4 months

Example 9

Patient swallowed two Norcos (1 Norco=10 mg hydrocodone+325 mgacetaminophen) 30 minutes prior to taking ¼ of an 8 mg tablet ofSuboxone sublingually. He took the ¼ of an 8mg tablet of Suboxonesublingually 3 times in day without experiencing any precipitatedwithdrawal. Norco is a short-acting narcotic; he was taking around 40-50mg of Norco/day.

Example 10

This patient was taking 100 mg of long-acting morphine (Kadian) twice aday and 30 mg of short-acting oxycodone (Roxicodone) 5 times a day. Hehad just taken 1 Kadian and 2 Roxicodones 45 minutes prior to taking ¼of an 8 mg tablet of Suboxone sublingually but experienced no withdrawalsymptoms. He took ¼ of an 8 mg tablet of Suboxone tablet sublingually 6more times that day without experiencing any withdrawal symptoms.

Example 11

This patient who had been previously placed on Suboxone had relapsed andwas receiving about 40 mg of Methadone from “the street.” She wasrestarted on ¼ of an 8 mg tablet of Suboxone taken twice a day and didnot experience any withdrawal symptoms in spite of having taken her lastdose of Methadone about 6 hours earlier.

Example 12

Seven patients diagnosed with bipolar II disorder and cyclothymia weredetermined to have initial GAF (global assessment of functioning) scoresranging from 31 to 60. Upon administration of Suboxone 8.0 mg twice aday and Geodon 40 mg once daily all seven patients experienced moodstabilization for three months or longer and an increase in GAF scoresover 80. Specifically, administration of this medication regimen hasresulted in mood stabilization for 12 months and an increase in GAFscore from 31-40 to 81-90 (patient 1), mood stabilization for 7 monthsand an increase in GAF score from 51-60 to 81-90 (patient 2), moodstabilization for six months and an increase in GAF score from 51-60 to81-90 (patient 3), an increase in GAF score from 31-40 to 81-90(patients 4 and 5), mood stabilization for 17 months and an increase inGAF score from 11-20 to 81-90 (patient 6), and mood stabilization forfour months and an increase in GAF score from 11-20 to 81-90.

Example 13

A patient diagnosed with mixed bipolar II disorder (depression and maniacharacterized by anxiety, impulsiveness, grandiosity, and pressuredspeech) and opioid-induced hypogonadism was initially determined to havea GAF score between 21-30. The patient was started on Suboxone 16 mg/dayand Seroquel 100 mg/day. After three months of treatment, the patientremained highly anxious, and had intermittent manic episodes although heis no longer depressed.

Example 14

A patient diagnosed with mixed bipolar I disorder was determined to havea GAF score between 11-20. The patient was extremely depressed and manicsimultaneously, with irritability, grandiosity, pressured speech,agitation, and impulsiveness coexisting with negative thoughts, guiltyfeelings, distractibility and suicidal ideation. She was in pain all thetime, and barely able to get out of bed. She was also dependent onmultiple narcotics. After treatment with 32 mg of Suboxone (8 mg fourtimes a day) and 40 mg of Geodon, her GAF score improved to between41-50. She also had more energy and less pain and was now able to getout of bed, but still felt highly anxious and manic for three months.Two months after increasing her Geodon to 120 mg, she is still stableand compliant with a GAF score between 71-80.

Example 15

A patient diagnosed with mixed bipolar I disorder (ultra rapid cycling)was initially determined to have a GAF score of between 0-10, and wasaddicted to multiple narcotics. She was also suicidal and completelynon-functional with rapidly alternating mood swings multiple times in aday. She always complained of fibromyalgia pain. Her psychiatrist wasgiving her Seroquel but that had elevated her blood sugar. Sincestarting Suboxone 32 mg/day and Geodon 120 mg/day and stopping Seroquel,her GAF score improved to 71-80, and has been maintained at this levelfor one year. The patient is able to get out of bed, has less pain, andher diabetes mellitus is better controlled.

Example 16

A patient diagnosed with bipolar I disorder was initially determined tohave a GAF score of 1-10. He was very depressed, in pain all the timeboth from the neuropathy and the fibromyalgia, and had attempted tooverdose on two occasions. His psychiatrist had placed him on threeantidepressants (Prozac, Elavil and Remeron) and 90 mg/day of Valium.After treatment with Suboxone 32 mg/day, Geodon 120 mg/day, Seroquel 25mg/day, Remeron 30 mg/day, and Valium 30 mg/day, his GAF score wasconsistently in the range of 71-80 for the past seven months. TheProzac, Elavil, and Remeron are being stopped, and he has decreased hisValium from 90 mg/day to 30 mg/day. He is no longer depressed butcomplains of anxiety and neuropathic pain. The plan is to discharge theSeroquel if possible and start an anti-epileptic both for theneuropathic pain and control of the bipolar disease.

Example 17

A patient diagnosed with bipolar I disorder was initially determined tohave a GAF score of 11-20. After treatment with Suboxone 8 mg four timesa day (32 mg total), and Seroquel 300 mg/day, the patient's GAF scorehas been consistently between 81-90 for 18 months.

Example 18

A patient diagnosed with mixed bipolar I disorder was initiallydetermined to have a GAF score of 21-30. She went to work everyday butsuffered from extreme depression alternating with manic periodscharacterized by financial profligacy, grandiosity and insomnia withracing thoughts. Her course was worsened by drug and alcohol addiction.She was started on 24 mg of Suboxone and 400 mg of Seroquel and becamemanic. The Suboxone was decreased to 16 mg and now she is stable with aGAF between 81-90 for the past two months. However, she complains ofexcessive sedation in the AM because of Seroquel, so the dose willprobably have to be lowered to 200 mg.

Example 19

This bipolar II patient presented for Suboxone maintenance. He wasalready taking Suboxone 8 mg twice a day, and his GAF score was 61-70.However, he suffered from extreme fatigue secondary to sleep apnea andopioid-induced low testosterone. Subsequently he was referred to a sleepclinic, started on CPAP, prescribed Seroquel 25 mg and testosteronereplacement. This patient is now doing wonderfully well with a GAFgreater than 90 over the past four months.

Example 20

A patient diagnosed with bipolar I disorder was initially determined tohave a GAF score of 31-40. After administering Suboxone 8 mg twice a dayfor four months, his GAF score improved to 61-70. However, he stillcomplained of depression. After addition of Seroquel 50 mg/day, his GAFscore has improved to 81-90 for four months.

Example 21

This high functioning patient diagnosed with bipolar II disorder wasinitially determined to have a GAF score of greater than 70. She wastaking Suboxone 8 mg twice a day, which was her maintenance dose.However, she began to show signs of hypomania—excessive talking,distraction, racing thoughts and insomnia. Thus, lithium 600 mg/day wasadded but the patient complained of side effects including tremulousnessand stomach discomfort along with diarrhea. On her own the patientdecreased the lithium dose to 300 mg and reported improvement in sideeffects. It is not clear whether she consistently takes the lithium,having consistently failed to get her blood levels checked.Nevertheless, she is stable and calmer with a GAF score of 80 for over ayear.

Example 22

This patient diagnosed with bipolar I disorder was initially determinedto have a GAF score of GAF of 21-30. He was addicted to hydrocodone, andvery depressed. He managed to hold on to a job but his attendance wassporadic because he did not have the energy to report to work. Afterstarting Zyprexa 5 mg/day and Suboxone 8 mg twice a day, his GAF scoreincreased to 71-80, and he has consistently gone to work for one month.The plan going forward will also be to treat his sleep apnea andhypogonadism.

Example 23

This was a patient with mixed bipolar I features in which symptoms ofsevere depression and mania existed simultaneously. She was a poorlyfunctioning patient with a GAF score between 0-10. She consistentlycomplained of severe fibromyalgia-type pain, was addicted to high dosesof morphine and repeatedly stated without expressing a specific plan toend her life and that she would be better off dead. Her GAF score hasnow been 51-60 for three months after starting Suboxone 8 mg four timesa day, and Seroquel 200 mg/day, and Zyprexa 5 mg/day. She is better ableto function and o longer expresses vague suicidal ideation.Conversations are more coherent because manic symptoms have abated andshe is no longer hypervoluble. The plan going forward is to treat hersleep apnea with CPAP.

Example 24

A patient diagnosed with mixed bipolar I disorder was initiallydetermined to have a GAF score of 31-40. This patient managed to holddown a job in spite of an addiction to painkillers and symptoms whichincluded fatigue, irritability, grandiosity, impulsivity,distractibility, hopelessness, helpless and feelings of guilt andworthlessness. At 16 mg of Suboxone he improved to a GAF score of 41-50for two months. While his manic symptoms disappeared, he was still verydepressed. The Suboxone was increased to 32 mg and the patient reportedthat his depression diminished but he felt highly anxious. His GAF scorewas still in the range of 41-50. Mood stabilizers were then started(Seroquel 400 mg/day), and the Suboxone dose was decreased to 24 mg. Henow has been functioning at a GAF score of 71-80 for four months. Hismajor complaint is extreme exhaustion which may be attributable to hissleep apnea and hypogonadism which need to be addressed going forward.

Example 25

This bipolar I patient (rapid cycling) was initially determined to havea GAF score of 1-10 and extreme manic behavior. With Suboxone alone (2mg/day), GAF score improved to 61-70. With Zyprexa 2.5 mg/day, GAF scoreimproved to 71-80. The patient has been stable and compliant for threemonths.

Example 26

This mixed bipolar I patient was compliant and stable with a GAF scoreof around 80 for four months. The treatment regimen included Suboxone 8mg twice a day and an antiepileptic (Lamictal 200 mg/day), which helpedthe bipolar symptoms and the pain from fibromyalgia. Due to financialconstraints the patient could no longer afford Suboxone.

Example 27

This bipolar II patient's presentation was marked by excessive fatigue.She was unable to stay awake during the day and had difficulty sleepingat night. She was ruled out for any other causes of fatigue includinganemia, underlying infection, narcolepsy, and sleep apnea. Her GAF scorewas initially 41-50. She was taking Methadone and Ritalin and was stableand compliant but exhausted and denied depression. Antidepressants didnot seem to help. After starting on Suboxone 8 mg twice a day her GAFimproved to 51-60. She reported a little more energy but not much. After2 months on Risperdal 4 mg/day and Suboxone 8 mg twice a day, she hasstopped Adderall, and her fatigue has virtually disappeared and herdemeanor is very bright and animated. Her GAF score had been 81-90 nowfor two months.

Example 28

This was an extremely dysfunctional schizoaffective patient, disheveled,addicted to narcotics and benzodiazepines, unable to hold down a job,with disorganized schizophrenic symptoms consisting of bizarre andunpredictable behaviors, and inability to hold a conversation. GAF scorehas been 71-80 for two months since starting on Suboxone 24 mg andTrilafon 8 mg three times a day.

Example 29

A patient diagnosed with mixed bipolar I disorder was initiallydetermined to have a GAF score of 11-20. With 16 mg of Suboxone and 5 mgof Zyprexa, the patient had an improved GAF score of 51-60, but wasstill depressed and experienced episodes of mania. Last month he wasincreased to Suboxone 24 mg/day. His GAF score is currently 61-70.

Example 30

This was a high functioning mixed bipolar II patient who presented withcoexistent dysthymia and insomnia, fatigue with racing thoughts, andirritability in the context of drug addiction. The patient is now stableand compliant with a GAF score greater than 90 for over six months on aregimen of Suboxone 8 mg twice a day and Neurontin 1800 mg/day.

Example 31

A patient diagnosed with mixed bipolar II disorder had an initial GAFscore of 61-70 with dysthymia, and extreme fatigue and insomnia withracing thoughts. After starting Suboxone 8 mg twice a day and Lyrica 50mg/day, the patient's GAF score has increased to 81-90, and has remainedstable at this level for 9 months.

Example 32

A patient diagnosed with mixed bipolar I disorder had an initial GAFscore of 11-20. The patient was simultaneously depressed and manic withan inability to sleep because of racing thoughts and an inability tocope with any stressful situation. On 4 mg/day of Suboxone for 18months, her GAF score was 31-40. She complained of extreme anxietytowards the evening. Now she is taking Suboxone 4 mg twice a day, andher GAF score has increased to over 80 for one month.

Example 33

A patient diagnosed with mixed bipolar I disorder had an initial GAFscore of 0-10, and had two previous suicide attempts. Since startingSuboxone 32 mg/day and Geodon 160 mg/day, her GAF has improved to 31-40for 6 months. She is still depressed but the depression is no longercatatonic and she no longer has suicidal thoughts. She was subsequentlystarted on Zyprexa 5 mg/day and her GAF improved to 75 for three months.The plan going forward is to treat the sleep apnea.

Example 34

This mixed bipolar I patient had a GAF score of 21-30 while takingSuboxone 16 mg/day. The patient suffered from anorexia, and alsodisplayed both manic and depressive symptoms. After starting Seroquel100 mg/day, the patient's GAF score has now been 71-80 for 13 months.The patient has also gained 8 lbs.

Example 35

This patient with rapidly cycling bipolar disorder initially presentedwith a GAF score of 11-20. The GAF score has been 61-70 for two monthsafter starting Suboxone 24 mg/day and Geodon 20 mg/day.

Example 36

This patient with rapidly cycling bipolar disorder initially presentedwith a GAF score of 31-40. The GAF score has been 81-90 for three monthsafter starting Suboxone 24 mg/day and Zyprexa 5 mg/day.

Example 37

This patient with rapidly cycling bipolar disorder initially presentedwith a GAF score of 31-40. The GAF score has been 71-80 for six monthsafter starting Suboxone 24 mg/day and Geodon 40 mg/day.

Example 38

A patient with bipolar II disorder (depression predominant), had aninitial GAF score of 51-60. The GAF score is now 71-80 with Suboxone 24mg/day and Seroquel 200 mg/day.

Example 39

This patient with bipolar I disorder had a GAF score of 11-21, and wasmanic appearing. The patient was already on Suboxone 24 mg/day, Lamictal300 mg/day, Gabapentin, Trazadone, and Geodon 200 mg/day. The Trazadone(antidepressant) was discontinued and in its place Seroquel 200 mg/dayand Zypexa 80 mg/day were started. Now the patient's mood is stabilizedand GAF score is 41-50.

Example 40

A patient with rapidly cycling bipolar disorder had an initial GAF scoreof 11-20. Upon taking Suboxone 16 mg/day for six months, their GAF scoreimproved to 51-60 but episodes of hypomania interspersed with depressionstill occurred. The Suboxone was increased to 32 mg/day. GAF score hassubsequently increased to 81-90 now for 6 months.

Example 41

This patient with mixed bipolar I disorder had an initial GAF score of21-30. For three months on Seroquel 100 mg/day and Suboxone 16 mg/day,the patient's GAF score improved to 61-70, but mixed episodes were stilloccurring. Geodon 40 mg/day was then started, and the patient's GAFscore improved to 71-80, which has now been stable for 7 months.

Example 42

This patient with mixed bipolar I disorder had an initial GAF score of21-30 and a history of crack cocaine addiction. His major complaint wasdifficulty sleeping due to racing thoughts. Geodon 80 mg/day andSuboxone 8 mg/day were started, but initially he could not tolerate theGeodon because it made him feel like he was “crawling out of his skin.”He was started on an antihistamine (Benadryl 1×/day) for akisthisia andreported significant improvement. His GAF score is now 81-90, and hasbeen stable for five months.

1-29. (canceled)
 30. A composition comprising (i) buprenorphine or apharmaceutically acceptable salt thereof and (ii) a second active agentin a single dosage form, wherein the second active agent comprises anantipsychotic agent, an atypical antipsychotic agent, an antiepilepticagent, lithium, a P-450 CYP3A4 inhibitor, a P-450 CYP2D6 inhibitor,salts and acids thereof, and combinations thereof. 31-35. (canceled) 36.The composition of claim 30, wherein the second active agent comprisesan atypical antipsychotic.
 37. The composition of claim 36, wherein theatypical antipsychotic is selected from the group consisting ofaripriprazole, arisuipride, olanzapine, paliperidone, quetiapine,risperidone, ziprasidone, and combinations thereof. 38-51. (canceled)52. A method for treating a bipolar condition and subtypes thereof in asubject, the subject experiencing at least one episode of racingthoughts, comprising administering buprenorphine or a pharmaceuticallyacceptable salt thereof to the subject to alleviate the racing thoughts.53. The method of claim 52, wherein the bipolar condition is bipolar Idisorder.
 54. The method of claim 52, wherein the bipolar condition isbipolar II disorder.
 55. The method of claim 52, wherein the bipolarcondition is mixed bipolar disorder. 56-59. (canceled)
 60. The method ofclaim 52, further comprising administering an opioid antagonist.
 61. Themethod of claim 60, wherein the opioid antagonist comprises naloxone.62. The method of claim 61, wherein the buprenorphine and naloxone areadministered together in a unit dose. 63-64. (canceled)
 65. The methodof claim 52, further comprising administering a second active agent tothe subject.
 66. The method of claim 65, wherein the second active agentis selected from the group consisting of antipsychotic agents, atypicalantipsychotic agents, antiepileptic agents, lithium, and salts and acidsthereof.
 67. The method of claim 66, wherein the second active agentcomprises an atypical antipsychotic agent selected from the groupconsisting of aripriprazole, olanzapine, paliperidone, quetiapine,risperidone, ziprasidone, arisulpride, and combinations thereof. 68-83.(canceled)
 84. The method of claim 52, wherein about 2.0 mg ofbuprenorphine is administered to the subject.
 85. The method of claim52, wherein about 8.0 mg of buprenorphine is administered to thesubject.
 86. A kit for treating a bipolar condition and subtypes thereofcomprising: a plurality of buprenorphine dosage forms; at least onesecond dosage form comprising a second active agent; a housing; andinstructions for taking the dosage forms for racing thoughts associatedwith the depressed phase of the bipolar condition or subtype thereof,and according to a predetermined dosing regimen, wherein the housing isconfigured to organize the dosage forms according to the predetermineddosing regimen. 87-94. (canceled)
 95. The kit of claim 86, wherein thesecond active agent is selected from the group consisting ofantipsychotic agents, atypical antipsychotic agents, antiepilepticagents, lithium, and salts and acids thereof.
 96. The kit of claim 95,wherein the second active agent comprises an atypical antipsychoticagent selected from the group consisting of aripriprazole, olanzapine,paliperidone, quetiapine, risperidone, ziprasidone, arisulpride, andcombinations thereof.
 97. (canceled)
 98. The kit of claim 86, comprisinga plurality of second dosage forms. 99-123. (canceled)
 124. The kit ofclaim 98, wherein the housing is configured to organize thebuprenorphine dosage forms and second dosage forms into morning dosageforms and evening dosage forms. 125-129. (canceled)